Thienopyrimidinedione derivatives as TRPA1 modulators

Abstract

The present invention is related to novel thienopyrimidinedione derivatives as TRPA (Transient Receptor Potential subfamily A) modulators. In particular, compounds described herein are useful for treating or preventing diseases, conditions and/or disorders modulated by TRPA1 (Transient Receptor Potential subfamily A, member 1). Also provided herein are processes for preparing compounds described herein, intermediates used in their synthesis, pharmaceutical compositions thereof, and methods for treating or preventing diseases, conditions and/or disorders modulated by TRPA1.

We claim: 
     
       1. A compound of the formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
       
       wherein,
 R 1  and R 2 , which may be the same or different, are independenly selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, (CR x R y )OR x , COR x , COOR x , CONR x R y , and (CH 2 ) n CHR x R y ; 
 R 3  is selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl; 
 L is a linker selected from —(CR x R y ) n —, —O—(CR x R y )-, —C(O)—, —NR x —,—S(O) m NR x —, —NR x (CR x R y )— and —S(O) m , NR x (CR x R y ) n ; 
 Z 1  and Z 2  are independently sulfur or CR a ; with a proviso that either of Z 1  or Z 2  is always sulfur; 
 R a  is selected from hydrogen, cyano, halogen, substituted or unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, OR x , (CR x R y ) n OR x , COR x , COOR x , CONR x R y , S(O) m NR x R y , NR x R y , NR x (CR x R y ) m OR x , (CH 2 )NR x R y , (CH 2 ) n CHR x R y , NR x (CR x R y ) n CONR x R y , (CH 2 ) n NHCOR x , (CH 2 ) n NH(CH 2 ) n SO 2 R x , (CH 2 ) n NHSO 2 R x , SR x  and OR x ; 
 U is selected from substituted or unsubstituted aryl, substituted or unsubstituted five membered heterocycles selected from the group consisting of thiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, pyrazole, imidazole, furan, thiophene, pyrrole, 1,2,3-triazole, and 1, 2, 4-triazole, or substituted or unsubstituted six membered heterocycle selected from the group consisting of pyrimidine, pyridine and pyridazine; 
 V is selected from hydrogen, cyano, nitro, —NR x R y , halogen, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, haloalkyl, haloalkoxy, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl, —C(O)OR x , —OR x , —C(O)NR x R y , —C(O)R x , and —SO 2 NR x R y ; or U and V together may form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring that may optionally include one or more heteroatoms selected from O, S and N; 
 at each occurrence, R x  and R y  are independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl; and 
 at each occurrence, ‘m’ and ‘n’ are independently selected from 0 to 2, both inclusive. 
 
     
     
       2. The compound according to  claim 1 , wherein L is CH 2 . 
     
     
       3. The compound according to  claim 1 , wherein R 1  and R 2  are (C 1 -C 4 )alkyl. 
     
     
       4. The compound according to  claim 3 , wherein (C 1 -C 4 )alkyl is methyl. 
     
     
       5. The compound according to  claim 1 , wherein R 3  is hydrogen. 
     
     
       6. The compound according to  claim 1 , wherein U is thiazole, imidazole, isoxazole, pyrazole, thiadiazole or pyrimidine. 
     
     
       7. The compound according to  claim 1 , wherein V is aryl. 
     
     
       8. The compound according to  claim 7 , wherein aryl is phenyl. 
     
     
       9. The compound of  claim 1  having the formula (Ia): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein,
 R 1  and R 2 , which may be the same or different, are independenly selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, (CR x R y ) n OR x , COR x , COOR x , CONR x R y , and (CH 2 ) n CHR x R y ; 
 R a  is selected from hydrogen, cyano, halogen, substituted or unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, OR x , (CR x R y ) n OR x , COR x , COOR x , CONR x R y , S(O) m NR x R y , NR x R y , NR x (CR x R y ) n OR x , (CH 2 ) n NR x R y , (CH 2 ) n CHR x R y , NR x (CR x R y ) n ,CONR x R y , (CH 2 ) n NHCOR x , (CH 2 ) n NH(CH 2 ) n SO 2 R x , (CH 2 ) n NHSO 2 R x , SR x  and OR x ; 
 U is selected from substituted or unsubstituted aryl, substituted or unsubstituted five membered heterocycles selected from the group consisting of thiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, pyrazole, imidazole, furan, thiophene, pyrrole, 1,2,3-triazole, and 1, 2, 4-triazole, or substituted or unsubstituted six membered heterocycle selected from the group consisting of pyrimidine, pyridine and pyridazine; 
 V is selected from hydrogen, cyano, nitro, —NR x R y , halogen, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, haloalkyl, haloalkoxy, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl, —C(O)OR x ,—OR x , —C(O)NR x R y , —C(O)R x , and —SO 2 NR x R y ; or U and V to ether may form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring that may optionally include one or more heteroatoms selected from O, S and N; 
 at each occurrence, R x  and R y  are independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, alkenyl, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl; and 
 at each occurrence, ‘m’ and ‘n’ are independently selected from 0 to 2, both inclusive. 
 
     
     
       10. The compound according to  claim 9 , wherein R 1  and R 2  are (C 1 -C 4 )alkyl. 
     
     
       11. The compound according to  claim 10 , wherein (C 1 -C 4 )alkyl is methyl. 
     
     
       12. The compound according to  claim 9 , wherein R a  is hydrogen or (C 1 -C 4 )alkyl. 
     
     
       13. The compound according to  claim 9 , wherein U is thiazole, imidazole, isoxazole, pyrazole, thiadiazole or pyrimidine. 
     
     
       14. The compound according to  claim 9 , wherein V is aryl. 
     
     
       15. The compound according to  claim 14 , wherein aryl is phenyl. 
     
     
       16. A compound having the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically-acceptable salt thereof 
         wherein R 1 , R 2  and R a , which may be the same or different, are each independently hydrogen or (C 1 -C 4 )alkyl; 
         R 4 , R 5 , R 6 , R 7 , R 8  and R 9 , which may be same or different, are each independently selected from the group comprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl. 
       
     
     
       17. The compound according to  claim 16 , wherein R 1  and R 2  are (C 1 -C 4 )alkyl. 
     
     
       18. The compound according to  claim 17 , wherein (C 1 -C 4 )alkyl is methyl. 
     
     
       19. The compound according to  claim 16 , wherein R 4  and R 5  are independently selected from the group consisting of hydrogen, fluoro, trifluoromethyl or trifluoromethoxy. 
     
     
       20. The compound according to  claim 16 , wherein R 6  and R 7  are independently selected from the group consisting of hydrogen, fluoro, trifluoromethyl or trifluoromethoxy. 
     
     
       21. The compound according to  claim 16 , wherein R 8  is hydrogen. 
     
     
       22. The compound according to  claim 16 , wherein R 9  is hydrogen. 
     
     
       23. The compound selected from:
 2-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)-N-[4-(trifluoromethyl)-1,3-thiazol-2-yl]acetamide; 
 N-[4-(4—Chlorophenyl)-1 ,3-thiazol-2-yl]-2-(1 ,3-dimethyl-2,4-dioxo-1 ,2,3 ,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide; 
 2-(1 ,3-Dimethyl-2,4-dioxo-1 ,2,3 ,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)-N-{4-[3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}acetamide; 
 2-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)-N-[4-(4-isobutylphenyl)-1,3-thiazol-2-yl]acetamide; 
 2-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)-N-{4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}acetamide; 
 2-(1,3-Dimethyl-2,4-dioxo-1,2,3 ,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)-N-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}acetamide; 
 2-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)-N-{4-[2-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}acetamide; 
 2-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)-N-{4-[3-fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}acetamide; 
 2-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)-N-{4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}acetamide; 
 2-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)-N-{4-[4-fluoro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}acetamide; 
 2-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)-N-{4-[3-fluoro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}acetamide; 
 N-[4-(3,4-Dichlorophenyl)-1,3-thiazol-2-yl]-2-(1 ,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide; 
 N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide; 
 [N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide]sodium; or 
 N-{4-[42,3-Difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
       24. The compound selected from:
 N-{4-[3,5-Difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide; 
 N-[4-(4-tert-Butylphenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide; 
 N-{4-[3-(Trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide; 
 N-[4-(4Chlorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide; 
 N-[4-(3,4-Difluorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide; 
 N-[4-(2,3-Difluorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide; 
 N-[4-(2,4-Difluorophenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide; 
 N-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide; 
 N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide; 
 N-{4-[4-Fluoro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide; 
 N-{4-[3-Fluoro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide; 
 N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide; 
 N-[4-(3-Trifluoromethoxyphenyl)-1H-imidazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide; 
 N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide; or 
 N-[4-(4-Cyanophenyl)-1,3-thiazol-2-yl]-2-(6-ethyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide;
 or a pharmaceutically acceptable salt thereof 
 
 
     
     
       25. The compound selected from:
 N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(6-ethyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide; 
 N-[4-(2,4-Difluoro -3-trifluoromethyl)phenyl)-1,3-thiazol-2-yl]-2-(6-ethyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide; 
 N-{4-[4-(Difluoromethoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl}-2-(6-ethyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide; 
 N-{4-[3,5-Difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl}-2-(6-ethyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide; 
 N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-6-propyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl) acetamide; 
 N-{4-[4-Difluoromethoxy-3,5-difluorophenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-6-propyl-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl) acetamide; 
 N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(6-isopropyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide; 
 N-[3-(4-Chlorophenyl)isoxazol-5-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide; 
 N-[5-(4-Bromophenyl)isoxazol-3-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide; 
 N-[1-(4-Bromophenyl)-1H-pyrazol-3-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide; 
 N-[3-(4-Chlorophenyl)-1H-pyrazol-5-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)acetamide; 
 N-[5-(4-Bromophenyl)-1,3,4-thiadiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide; 
 N-[4-(4-Bromophenyl)pyrimidin-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide; 
 2-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)-N-[4-(4-isobutylphenyl)-1,3-thiazol-2-yl]acetamide; or 
 N-[4-(4-Chlorophenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)acetamide; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
       26. The compound selected from:
 2-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)-N-[4-(3-trifluoromethyl)phenyl]-1,3-thiazol-2-yl]acetamide; 
 2-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)-N-[4-(4-trifluoromethyl)phenyl]-1,3-thiazol-2-yl]acetamide; 
 2-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)-N-{4-[3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}acetamide; 
 2-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)-N-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}acetamide; 
 2-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)-N-{4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}acetamide; 
 2-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)-N-{4-[2-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}acetamide; 
 2-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)-N-{4-[3-fluoro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}acetamide; 
 N-[4-(3,4-Dichlorophenyl)-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)acetamide; 
 2-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)-N-{4-[3-fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}acetamide; 
 2-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)-N-{4-[4-fluoro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}acetamide; 
 N-{4-[2,3-Difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)acetamide; 
 N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)acetamide; 
 N-{4-[3,5-difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)acetamide; 
 N-{4-[4-(Difluoromethoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)acetamide; or 
 N-{4-[3,5-Difluoro-4-(2,2,2-trifluoro-ethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidin-5-yl)acetamide; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
       27. A pharmaceutical composition comprising one or more compounds selected from the compound(s) of  claim 1 , and one or more pharmaceutically acceptable excipients, carriers, diluents or mixture thereof. 
     
     
       28. A method for relieving the symptom or inhibiting, arresting or reducing a disease or condition associated with TRPA1 function in a subject in need thereof comprising administering to the subject an effective amount of a compound according to  claim 1  wherein the disease or condition is selected from chronic pain, neuropathic pain, osteoarthritic pain, COPD and asthma. 
     
     
       29. A compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       30. A pharmaceutical composition comprising the compound of  claim 29 , and one or more pharmaceutically acceptable excipients, carriers, diluents or mixture thereof. 
     
     
       31. A method for relieving the symptom or inhibiting, arresting or reducing a disease or condition associated with TRPA1 function in a subject in need thereof comprising administering to the subject an effective amount of a compound according to  claim 29  wherein the disease or condition is selected from chronic pain, neuropathic pain, osteoarthritic pain, COPD and asthma.